Oligonucleotide analogs having cationic intersubunit linkages
AssigneeAVI BioPharma, Inc.
InventorsDwight D. Weller, Jed N. Hassinger, Bao Zhong Cai
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Abstract
Morpholino oligomers containing both uncharged and cationic intersubunit linkages are provided. The oligomers are oligonucleotide analogs containing predetermined sequences of base-pairing moieties. The presence of the cationic intersubunit linkages in the oligomers, typically at a level of about 10-50% of total linkages, provides enhanced antisense activity, in various antisense applications, relative to the corresponding uncharged oligomers. Also provided are such oligomers conjugated to peptide transporter moieties, where the transporters are preferably composed of arginine subunits, or arginine dimers, alternating with neutral amino acid subunits.
Claims16
An oligomer comprising a sequence of morpholino subunits, each morpholino subunit comprising a base-pairing moiety, such that the oligomer can bind in a sequence-specific manner to a target nucleic acid, wherein the morpholino subunits are each joined by a phosphorus-containing intersubunit linkage having the structure:
- wherein:
- W is S or O;
- X is NR1R2 or OR6;
- Y is O or NR7;
- and the intersubunit linkage is, at each occurrence, independently:
- linkage (a), where each of R1, R2, R6 and R7 is independently hydrogen or lower alkyl;
- or
- linkage (b1), where X is NR1R2, Y is O and NR1R2 is a piperazino group, such that R1R2 is —CHRCHRN(R3)(R4)CHRCHR—, wherein:
- each R is, at each occurrence, independently H or CH3;
- R4 is H, CH3 or an electron pair;
- and
- R3 is H, lower alkyl, —C(═NH)NH2, —Z-L-NHC(═NH)NH2 or —[C(O)CHR′NH]mH, where Z is carbonyl (C(O)) or a direct bond, L is an optional linker up to 18 atoms in length comprising alkyl, alkoxy or alkylamino groups, or combinations thereof, R′ is a side chain of a naturally occurring amino acid or a one- or two-carbon homolog thereof, and m is 1 to 6;
- and at least one intersubunit linkage is linkage (b1).
Dependencies are inferred from the claim text.